The review concluded that the majority of patients using opioids for chronic non-malignant pain experience at least one adverse event, and that a significant proportion stop using them because of an adverse event. The conclusion appears to follow from the evidence presented, although lack of detail about the methods and the short duration of the trials make it difficult to verify the findings.

Authors' objectives

To determine the prevalence of opioid adverse events in chronic non-malignant pain (CNMP); to identify major differences in opioid adverse events in CNMP of different aetiology; and to determine how much information is lost by limiting the analyses to placebo-controlled trials only.

Searching

MEDLINE, EMBASE and the Cochrane Library (all until August 2004), the Oxford Pain Relief Database (from 1950 to 1994) and the bibliographies of retrieved citations were searched without any language restrictions. The search terms used were not reported. Abstracts and unpublished reports were excluded.

Study selection

Study designs of evaluations included in the review

Randomised double-blind controlled trials (RCTs) with at least 10 adult patients completing each treatment arm and an appropriate randomisation method were eligible for inclusion. The follow-up period ranged from 3 days to 8 weeks. The majority of the studies had a duration of 4 weeks or less.

Specific interventions included in the review

Studies of opioids compared with placebo or any other analgesic administered for CNMP were eligible for inclusion. The intervention included any opioid administered by an oral route, alone or in combination with other analgesics. The included studies were of codeine, dextropropoxyphene or tramadol, both with and without paracetamol, dihydrocodeine, morphine, meptazinol, oxycodone and pentazocine. The majority of the studies did not report initial dose titration. The comparator was placebo, paracetamol, diclofenac or nortriptyline.

Participants included in the review

Participants with CNMP were eligible for inclusion. The participants in the included studies had mainly arthritis or other musculoskeletal diseases; some patients had neuropathic pain and pain of mixed origin.

Outcomes assessed in the review

Studies reporting data on adverse events were eligible for inclusion. The outcomes of interest were the number and percentage of patients with any adverse events or a particular adverse event. Most of the included studies collected volunteered information on adverse events or asked general questions. Very few used diaries or questionnaires.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

The validity of the trials was assessed according to the 3-item Jadad criteria: quality of randomisation, double-blinding, and the reporting of withdrawals and drop-outs. The quality score could range from 1 to 5.

The authors did not state how the papers were assessed for validity, or how many reviewers performed the validity assessment.

Data extraction

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Data were extracted on the numbers randomised and analysed, the type and dose of opioid, study duration, withdrawals due to adverse event or lack of efficacy, the number of patients with any adverse events, and number of patients with a particular adverse event.

Methods of synthesis

How were the studies combined?

The studies were discussed in a narrative synthesis. The percentage of patients experiencing any adverse event or a particular adverse event, as well as the percentage of patients who withdrew due to adverse events or lack of effects, was calculated and compared in opioid and placebo groups with 95% confidence intervals (CIs).

How were differences between studies investigated?

The data were analysed for all patients, irrespective of their condition, and for patients with arthritis, other musculoskeletal pain, neuropathic pain and pain of mixed origin. The possible reasons for heterogeneity were discussed, including type, dose and duration of drug, titration regimen and methods used to collect information on adverse events.

Results of the review

Thirty-four RCTs (n=5,546) were included, of which 4,212 patients contributed data on opioid adverse events to the analysis. Sixteen trials had a placebo control.

Oral opioid compared with placebo.

The rate of adverse events varied widely among the trials, particularly between the small trials. Overall, the rate of patients experiencing any adverse event or a particular adverse event was higher for opioids than placebo. On average, 51% of patients in an intervention group experienced one or more adverse events (95% CI: 49, 53), compared with 30% in a placebo group (95% CI: 26, 34). The rates for each type of adverse event were as follows: dry mouth, 25% for intervention group versus 3.2% for placebo group; nausea, 21% versus 5.6%; constipation, 15% versus 5%; dizziness, 14% versus 4.5%; drowsiness or somnolence, 14% versus 4%; pruritus, 13% versus 2.1%; and vomiting, 10% versus 2.4%.

Withdrawal due to adverse events was 22% in the intervention group (95% CI: 21, 23) and 7.1% in the placebo group (95% CI: 5.2, 8.9). Withdrawal due to lack of efficacy was 6.5% in the intervention group (95% CI: 5.6, 7.4) and 20% in the placebo group (95% CI: 17, 23).

There was no obvious relationship between the opioid type, dose or dosing regimen and the rate of adverse events. Different painful conditions produced similar patterns of results. All but one trial had a quality score of 3 or more out of 5.

Oral opioid compared with any comparator. The inclusion of trials without a placebo comparator increased the potential amount of data by 1.4 times. The authors did not compare opioid with other comparators; however further analyses on withdrawals and prevalence of adverse events from trials with any comparator and for patients with arthritis, musculoskeletal pain, neuropathic pain and pain of mixed origin were reported in additional files presented with the paper.

Authors' conclusions

Most patients using opioids for CNMP experience at least one adverse event and a substantial proportion of them do not continue opioid use because of adverse events, although these findings should be interpreted with caution as most trials had a short-term follow-up.

CRD commentary

The review question and inclusion criteria were clear, but the authors did not adequately describe how they performed the study selection, quality assessment and data extraction processes. The search strategy was restricted to published articles and the search terms were not reported, thus relevant studies might have been missed and the possibility of publication bias cannot be ruled out. Although study quality was high in most trials, this does not necessarily mean that the quality of reporting adverse events was high. Inadequate reporting of adverse events may be common even in high-quality trials. Since most of the trials had a short-term follow-up and many were small they might not have detected all adverse events, particularly rare adverse events and adverse events occurring long after the intervention.

The authors discussed possible reasons for heterogeneity and provided summary results for patients with different conditions. In real clinical life the opioid dose is typically titrated. However, most of the included studies did not titrate the opioid used, so the results may have limited applicability. A significant proportion of patients withdrew due to adverse events or lack of effects. This might have resulted in an underestimation of the rate of adverse events. Overall, the authors' conclusion about the rate of adverse events appears to be supported by the evidence presented, although it was not possible to verify this given the lack of detail concerning the methods, the short duration of follow-up, the small number of participants, and the possible differences between the trials and real clinical practice.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that future research should consider a number of variables, including dose and duration of opioid used, severity of pain and whether the opioid was titrated. The studies should also have longer follow-up.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.